Steroidal 2beta, 3alpha-diol cyclic trithiocarbonate



This invention relates to steroids and production thereof. Moreparticularly, it relates to steroidal cyclic trithiocarbonates andproduction thereof.

The said steroidal cyclic trithiocarbonates are intended to mean thesteroids having the partial structural formula:

It is an object of the present invention to embody the said steroidalcyclic trithiocarbonates. Another object of this invention is to embodya generally applicable process for the conversion of a2,3-epithio-steroid into the corresponding cyclic trithiocarbonate. Afurther object of this invention is to embody steroidal cyclictrithiocarbonates having specific pharmacological activities. These andother objects will be apparent to those skilled in the art to which thepresent invention pertains from the subsequent description.

The process of the present invention is representable by the followingpartial formula scheme showing only the A-ring of the steroid skeleton:

wherein the ripple mark represents CC- or fi-configuration.

The process of the present invention is generally applicable to2,3-epithio-steroids having the partial structure of Formula II. Thesteric configuration of the epithio group on the A-ring of the starting2,3-epithio-steroid has substantially no effect on the reaction; thatis, the epithio group may have ccor fl-configuration. Furthermore, suchsubstituents which do not exert any substantial effect on the reaction,as ll-hydroxyl, l6-alkyl and 17-side chain, may exist at any positiononthe B-, C- or D-ring of the starting material. Examples of2,3-epithio-steroids available as starting compounds include2a,3a-epithio-Sa-chOlestane, 218,3B-epithio-Sa-cholestane,20,3oc-8PlthlO-50c-Ch013lll0 acid, methyl 2,8,3B-epithio-5a-cholanate,2a,3a-epithio-ZSD-Sa-spirostane, 2,8,3B-epithio-5a-androstan-17,8-0117-acetate, 20c,3a-GPithiO-Sa-aIIdIOStaH-17,3-01 l7-propionate2p,3B-epithio-5a-androstan-17-one, 200,3 a-epithio-5a-pregnane-11B,17oc,21[1i0l 21-acetate, 20:,3a-epithio-5a-pregnan-20-one,25,3,8-epithio-5a-pregnan-1 lfl-ol-ZO-one,2;3,3/i'-epithio-5a-pregnane-1lB,17a,2l-triol-20-one, 28,3/3-epithio-5a-pregnane-l1fi,17a,2l-triol-2O-one 21- acetate, etc.

.i 3,13%,128 Patented Feb. 9, 1965 These 2,3-epithio-steroids can beprepared from the corresponding 2,3-epoxy-steroids according to thefollowing scheme showing only the A-ring of the steroid skeleton:

/ thioeyanie x acid 0 A base (e.g. alllkaili n gtal y roxi c inloweralkanol A S A thioeyanie acid 0 A base (e.galkadli install my fox] 6 inlower HO alkanol A S A N CS" According to the process of the presentinvention, the starting 2,3-epithio-steroid is reacted with alkali metalo-(lower) alkyldithiocarbonate while heating (usually refluxing) to givethe corresponding cyclic trithiocarbonate. The alkali metalo-(lower)alkyldithiocarbonate is readily prepared by mixing carbondisulfide, lower alkanol (e.g. methanol, ethanol, propanol) and alkalimetal (e.g. sodium, potassium), and the thus-prepared alkali metal 0-(lower)alkyldithiocarbonate solution may be employed in the process ofthe present invention as it is.

The thus-obtained cyclic trithiocarbonates having the partial structureof Formula I exhibit specific pharmacological activities, For instance,17/3-acetyloxy-5oc-androstane-2,8,3a-diol cyclic trithiocarbonateproduced marked inhibition of gonadotropin at a total dose of 1milligram in the test using mice. Accordingly, these products may beuseful as controlling agents for diseases of menopause,ovulation-inhibition agents and controlling agents for hypergonadism orprecocious puberty.

The following examples set forth illustratively presentlypreferredembodiments of the invention. In these examples, mg.=milligram(s),g.=gram(s), and ml.=milli- 1itre(s). Other abbreviations each have aconventional meaning.

EXAMPLE 1 To a solution of potassium hydroxide (7 g.) in a mixture ofmethanol (50 ml.) and carbon disulfide (17 ml.), there is added25,3B-epithio-u-cholestane (2.070 g.), and the resultant mixture isrefluxed for 24 hours. After driving out carbon disulfide, water isadded to the reaction mixture. The precipitated substance is collectedby filtration and chromatographed on alumina (60 g.). The eluate (1.940g.) from a mixture of petroleum ether and benzene (19:19:1) iscrystallized from a mixture of ether and ethanol to give5a-cholestane-2p,3a-diol cyclic trithiocarbonate (1.318 g.) as yellowleaflets melting at 132 to 133 C.

U.V.: A232? 319 my. (e:16,310). I.R.: 1123i? 1062 omf Analysis.--Calcd.for C H S C, 70.23; H, 9.68; S, 20.09. Found: C, 70.30; H, 9.77; S,20.19.

The starting material of this example, 2/3f3B-epithio-5acholestane, canbe prepared by reacting 2a,3oc-epOXy-5occholestane [Fieser et al.:Steroids, page 254] with an ethereal solution of thiocyanic acid at roomtemperature (around 15 0.), followed by refluxing the resultant 2 8-thiocyanato-3a-hydroxy-5a-cholestane with potassium hydroxide inethanol.

EXAMPLE 2 Preparation of Sa-cholestane-2/3,3a-di0l cyclictrithiocarbonate To a solution of potassium hydroxide (4 g.) in amixture of methanol (30 ml.) and carbon disulfide ml.), there is added20;,3 u-epithio-5a-cholestane (949 mg), and the resultant mixture isreacted and treated as in Example 1 to give 5a-cholestane-2p,3a-diolcyclic trithiocarbonate (545 mg.) as yellow leaflets melting at 132 to133 C.

The starting material of this example, 20,3oc-6PithiO-5occholestane, canbe prepared by reacting 2fl,35-epoxy-5acholestane [Fieser et al.:Steroids, page 252] with an ethereal solution of thiocyanic acid at roomtemperature (around 0.), followed by refluxing the resultant 2B-hydroxy-3a-thiocyanato-5a-cholestane with potassium hydroxide inmethanol.

EXAMPLE 3 Preparation of 17B-acetyloxy-Sa-undrostam-Zfija-diol cyclictrithiocarbonate 8/ r of m To a solution of potassium hydroxide (5 g.)in a mixture of methanol (30 ml.) and carbon disulfide (12 1111.), thereis added 2B,3B-epithio-5oc-androstan-1713-01 17- acetate (1.407 g.), andthe resultant mixture is refluxed for 43 hours. After addition of waterto the reaction mixture, the resultant mixture is shaken withchloroform. The chloroform extract is washed with water, dried andevaporated. The residue (1.453 g.) is mixed with pyridine (10 ml.) andacetic anhydride (5 ml.), allowed to stand overnight and treated in aconventional manner to give an amorphous substance (1.478 g.). Thissubstance is chromatographed on alumina (40 g.). The eluate (946 mg.)from a mixture of petroleum ether and benzene (4:1, 2:1, 1:1) iscrystallized from ether and recrystallized from a mixture of chloroformand ethanol to give 17fi-acetyloxy-5u-androstane-2{3,3a-diol cyclictrithiocarbonate (800 mg.) as yellow leaflets melting at 199 to 200 C.

I l H H U.V.: X5322? 320 mu (e:l6,820). 1066 Analysis.Calcd. for C H O SC, 62.22; H, 7.60; S, 22.65. Found: C, 62.05; H, 7.62; S, 22.54.

The starting material of this example, 25,3,B-epithio-5aandrostan-178-ol 17-acetate, can be prepared by reacting2a,3a-epoxy-Sa-androstan-l7,8-01 17-acetate [J Fajkos et al.: Chem.Abstracts, vol. 53, page 5342 (1959)] with an ethereal solution solutionof thiocyanic acid at room temperature (around 15 C.), followed byrefluxing the resultant 2fi-thiocyanato-3a-hydroXy-Sa-andrOstan-I7 3-01l7-acetate with potassium hydroxide in ethanol.

In the similar manner, there are obtained other 17,8- loweralkanoyloxy-Sa-androstane-2,l3,3a-diol cyclic trithiocarbonates such as17 B-propionyloxy-S u-androstane-2p,3adiol cyclic trithiocarbonate and17fi-butyryloxy-5oz-androstane-2/3,3ar-diol cyclic trithiocarbonate.

What is claimed is:

1. Process for preparing a steroidal cyclic trithiocarbonate whichcomprises reacting a steroid wherein the A ring is substituted asfollows:

and which is selected from the group consisting of 200,302-epithio-5a-cholestane, 25,3p-epithio-5a-cholestane, 2a,3a-

epithio-5a-cholanic acid, methyl 2fi,3fl-epithio-5a-cholan-- thecorresponding steroid wherein the A ring is substituted as follows:

2. Process for preparing a steroidal cyclic trithiocarbonate whichcomprises reacting a steroid wherein the A ring is substituted asfollows:

3. A 2fl,3lx-cyclic trithiocarbonate of a member selected from the groupconsisting of 5a-cholestane, 5u-cholanic acid, methyl 5a-cho1anate,25D-5a-spirostane, Sat-androstan-17fi-ol 17-acetate,5a-androstan-17,8-o1 17-propionate, Sa-andrQstan 17 one, Saregnane-IlB,l7a,2l-t1i01 21- 6 acetate, Sa-pregnan-ZO-one,Sa-pregnan-l15-ol-20-one, pregnane-l1/3,17ot,2l-triol-20-one, andSa-Pregnane-IlB, 17u,'21-triol-20-one ZI-acetate.

4. A steroid having the following formula:

fr wherein R is lower alkanoyl.

S. A steroid having the following formula:

OCOOH;

6. A steroid having the following formula:

r I I I S fr References Cited in the file of this patent Lightner etal.: Chemistry and Industry, No. 27, July 27, 1962, pp. 1236-1237.

3. A 2B,3A-CYCLIC TRITHIOCARBONATE OF A MEMBER SELECTED FROM THE GROUPCONSISTING OF 5A-CHOLESTANE, 5A-CHOLANIC ACID, METHYL 5A-CHOLANATE,25D-5A-SPIROSTANE, 5A-ANDROSTAN-17B-OL 17-ACETATE, 5A-ANDROSTAN-17B-OL17-PROPIONATE, 5A-ANDROSTAN - 17 - ONE, 5A-PREGNANE-11B,17A,21-TRIOL21ACETATE, 5A-PREGNAN-20-ONE,5A-PREGNAN-11B-OL-20-ONE,5APREGNANE-11B,17A,21-TRIOL-20-ONE, AND 5A-PREGNANE-11B,17A,21-TRIOL-20-ONE 21-ACETATE.